1. Field Of The Invention
The invention relates to a process for the production of optically pure 2,2-dimethylcyclopropanecarboxylic acid by resolution of racemates.
2. Background Art
The amide of 2,2-dimethylcyclopropanecarboxylic acid is an important intermediate product for the synthesis of the enzyme inhibitor cilastatin (European Published Patent Application No. 0048301).
Especially for the production of pharmaceutical active ingredients, it is desirable to have 2,2-dimethylcyclopropanecarboxylic acid available in optically pure form, i.e., in the form of the pure (S)-(+) or pure (R)- (-) enantiomer. Since the chemical synthesis of 2,2-dimethylcyclopropanecarboxylic acid yields the compound in the form of its racemate, it is necessary to perform a resolution of this racemate. Such resolutions of racemates are usually performed by first the enantiomer mixture to be separated being converted by an optically active auxiliary substance into a mixture of diastereomeric derivatives which, because of the different physical properties of diastereomers, can be separated by fractional crystallization or chromatography. In the ideal case, a pure enantiomer of the compound to be separated and the optically active auxiliary substance are released from the thus-separated diastereomers.
Actually, with a given auxiliary substance, even if it is optically completely pure, only the incomplete separation of one pure enantiomer is achieved in most cases, so that a mixture remains, which consists predominantly of the other enantiomer. In less favorable cases, neither of the two enantiomers can be isolated in pure form. As derivatives of carboxylic acids for resolution of racemates, their salts with optically active bases, especially amines, are often used. These salts have the advantage that they are formed very easily and quickly and can also again be cleaved by the addition of a strong acid. For resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid, already (S)-(-)-1-phenylethylamine (British Patent No. 1,260,847), (-)-N-methylephedrine (Japanese Published Patent Application Nos. 60-56936 and 60-56942), quinine (European Published Patent Application No. 0 161 546), and various 1,2-diphenylethylamines (European Published Patent Application No. 0 039 511) have been used.
With 1-phenylethylamine neither a satisfactory yield nor an adequate optical purity could be achieved. Quinine yielded enantiomer in good optical purity but poor yield, no yield was indicated for N-methylephedfine With 1,2-diphenylethylamine the yield is satisfactory and the optical purity very good but the reagent, as is also N-methylephedrine is very expensive. Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers by the diastereomeric menthyl esters, which can be obtained from the acid chloride with (+) or (-) menthol (U.S. Pat. No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in working up and requires the relatively expensive menthol.